A major limitation in developing prosthetic implants for medical use is that most prosthetic materials thus far developed tend to be excessively thrombogenic, i.e. they trigger excessive blood clot formation, or thrombosis, at surfaces of the implant exposed to the patient's blood. This problem can lead to severe complications, particularly in the case of prosthetic vascular grafts used to correct coronary artery disease, lower limb ischemia, arterial aneurysms and other circulatory problems. About 20% to 30% of patients undergoing vascular bypass or replacement surgery require prosthetic grafts, because autologous veins are unavailable due to previous surgery or other reasons. In these patients, there is a high rate of graft failure due to the high thrombo genicity of synthetic materials used to produce the prosthetic grafts. One multicenter study demonstrated that the cumulative 4-year patency of prosthetic grafts used for distal arterial reconstruction was only 12% for polytetrafluoroethylene (PTFE) grafts; far lower than the long-term patency observed for autologous grafts. Vieth et al. (J. Vase. Surg. 3: 104-114, 1986).
The mechanism by which thrombosis occurs in prosthetic vascular grafts is generally well understood. Shortly after implantation of a synthetic graft, adsorption and accumulation of blood proteins on the lumenal surface of the graft begins. In particular, a surface coating of polymerized fibrin, referred to as the pseudointima, appears first, followed by an accumulation of thrombin bound to the fibrin. The thrombin contributes to platelet activation and formation of a platelet rich thrombus. Bound thrombin may also contribute to further fibrin accretion that in turn leads to distal embolism.
An important difference between prosthetic and autologous vascular grafts is that prosthetic grafts lack a lining of endothelial cells which cover the lumenal surface of natural vessels. It is widely believed that the endothelial lining provides an anti-thrombogenic effect and is among the most important factors in maintaining long term patency in autologous grafts. Accordingly, numerous attempts have been made to artificially seed endothelial cells onto surfaces of prosthetic grafts. (reviewed by Mosquera and Goldman, Br. J. Surg. 78: 656-660, 1991 ). Most of these efforts involved coating the prosthetic surface with a "biological glue," comprised of adhesive proteins and other materials which enhance endothelial cell adhesion and growth. These investigations have used a variety of extracellular matrix proteins and other materials, including fibrin, fibrin gels cross-linked with factor XIII, fibronectin, laminin, various forms of collagen, albumen and blood. Although endothelial seeding of grafts has shown beneficial results in experimental settings, the technology has not progressed sufficiently that seeded grafts suitable for routine use can be produced.
Another primary focus of research concerning prosthetic vascular grafts has involved efforts to develop non-cellular, anti-thrombogenic coatings, such as protein coatings, which may reduce the thrombogenicity of implanted grafts. One such study involved coating prosthetic surfaces with the anticoagulant protein heparin. Nagaoka et al. (Artificial Organs 17: 598-601, 1983). Other studies have used natural, extracellular matrix materials to coat vascular grafts. For example, European Patent No. 0 366 564 issued to Sawamoto et al. discloses polymeric materials coated with a hydrolyzed fibrin layer optionally cross-linked with factor XIII. In addition, U.S. Pat. No. 5,324,647 issued to Rubens et al. discloses polymeric materials coated with either a layer of fibrinogen, thermally denatured fibrinogen or factor XIII cross-linked fibrin. While various of these natural coatings are reported to have anti-thrombogenic effects, prosthetic materials treated with such methods have not yet been widely employed in a clinical setting.
In view of the above, there is a clear need in the art for prosthetic materials having improved biological compatibility over currently available materials. In particular, there is a need for prosthetic materials which have reduced thrombogenicity compared to available synthetic materials used for prostheses. Such materials should be resistant to the deposition of blood proteins and to platelet adherence. These materials would be useful for producing vascular grafts, synthetic heart valves, artificial organs and in any other application where a surface of the prosthetic material will be exposed to a patient's blood, so as to create a potential for thrombogenesis at the exposed prosthetic surface. The present invention provides such materials, as well as methods for preparing those materials. Materials prepared in accordance with the methods of the invention are useful for providing biocompatible implants, medical treatment methods employing such implants, as well as useful materials for experimental modeling of thrombogenic and fibrinolytic processes.